Intractable targets (often termed “undruggable”) are proteins or biological molecules heavily implicated in diseases (particularly cancer) that cannot be easily modulated by conventional small molecule drugs. They are considered challenging because they lack defined, deep binding pockets required for traditional drugs to attach and inhibit function. They often involve protein-protein interactions (PPIs), transcription factors, and intrinsically disordered proteins.
Progressing “intractable targets” requires a hybrid approach combining novel chemistry with advanced DMPK to navigate non-Rule of 5 (bRo5) chemical space. Success hinges on employing targeted covalent modification to enhance selectivity and to transform shallow binding pockets into druggable sites, and using degradation technologies to shift from occupancy-based to event-driven pharmacology (degradation) allowing targeting undruggable proteins. While intractable targets require non-traditional chemistry, DMPK is not a downstream filter. Cross-functional integration between medicinal chemists and DMPK scientists is critical to address non-traditional physicochemical properties early.
In this presentation, we will illustrate that ADME strategies traditionally used for selecting reversible inhibitors may not be appropriate for the discovery and development of covalent inhibitors. Non-traditional assays in combination with “adequate” PK profiles are the critical considerations for progression of such compounds. Proteolysis-targeting chimeras (PROTACs) represent an emerging therapeutic modality. Their bifunctional design inherently leads to physicochemical properties that often lie beyond the limits for traditional oral small molecules. We will highlight the key challenges in optimizing oral PROTACs and discuss the need for alternative experimental approaches to accurately characterize their atypical ADME properties.
Jing Zhang, Director of Scientific Engagement. BioDuro
